Betancourt Angela M, Burgess Shane C, Carr Russell L
Center for Environmental Health Sciences, College of Veterinary Medicine, Mississippi State University, 39762, USA.
Toxicol Sci. 2006 Aug;92(2):500-6. doi: 10.1093/toxsci/kfl004. Epub 2006 May 4.
Chlorpyrifos (CPS), a known neurotoxicant, is a widely used agricultural organophosphorus insecticide. The effects of postnatal exposure to CPS on the expression of mRNA for two factors critical to brain development, nerve growth factor (NGF) and reelin, were investigated in the forebrain of rats. In addition, the expression of mRNA for the muscarinic acetylcholine receptor (mAChR) M(1) subtype and cell-specific markers for developing neurons (beta-III tubulin), astrocytes (glial fibrillary acidic protein, GFAP), and oligodendrocytes (myelin-associated glycoprotein, MAG) was also investigated. Oral administration of CPS (1.5 or 3.0 mg/kg) or the corn oil vehicle was performed daily from postnatal days (PNDs) 1 through 6. No signs of overt toxicity or of cholinergic hyperstimulation were observed after CPS administration. Body weight was significantly different from controls on PND7 in both males and females exposed to 3.0 mg/kg CPS. Quantitative PCR was performed on the forebrain. The expression of NGF, reelin, and M(1) mAChR mRNA was significantly reduced with both dosages of CPS in both sexes. beta-III Tubulin mRNA expression remained unchanged after exposure, whereas MAG mRNA expression was significantly decreased with both dosages of CPS in both sexes, suggesting effects on the developing oligodendrocytes. In contrast, GFAP mRNA levels were significantly increased with both dosages of CPS in both sexes, suggesting increased astrocyte reactivity. Our findings indicate that dosages of CPS which cause significant cholinesterase inhibition but do not exert overt toxicity can adversely affect the expression levels of critical genes involved in brain development during the early postnatal period in the rat.
毒死蜱（CPS）是一种已知的神经毒物，是一种广泛使用的农用有机磷杀虫剂。本研究调查了出生后接触CPS对大鼠前脑中两个对脑发育至关重要的因子——神经生长因子（NGF）和Reelin——的mRNA表达的影响。此外，还研究了毒蕈碱型乙酰胆碱受体（mAChR）M（1）亚型以及发育中神经元（β-III微管蛋白）、星形胶质细胞（胶质纤维酸性蛋白，GFAP）和少突胶质细胞（髓鞘相关糖蛋白，MAG）的细胞特异性标志物的mRNA表达。从出生后第1天到第6天，每天对大鼠口服CPS（1.5或3.0 mg/kg）或玉米油赋形剂。给予CPS后未观察到明显的毒性迹象或胆碱能过度刺激。在暴露于3.0 mg/kg CPS的雄性和雌性大鼠中，出生后第7天的体重与对照组有显著差异。对前脑进行定量PCR。两种剂量的CPS均使雌雄两性的NGF、Reelin和M（1）mAChR mRNA表达显著降低。暴露后β-III微管蛋白mRNA表达保持不变，而两种剂量的CPS均使雌雄两性的MAG mRNA表达显著降低，表明对发育中的少突胶质细胞有影响。相反，两种剂量的CPS均使雌雄两性的GFAP mRNA水平显著升高，表明星形胶质细胞反应性增加。我们的研究结果表明，导致显著胆碱酯酶抑制但未产生明显毒性的CPS剂量，可在大鼠出生后早期对参与脑发育的关键基因的表达水平产生不利影响。
